1. Technical Field
This disclosure generally relates to compounds and compositions, and methods of using these compounds and compositions, as inhibitors of human immunodeficiency virus (HIV) replication, and methods of treating patients infected with HIV, the causative agent of acquired immunodeficiency syndrome (AIDS). The present disclosure also relates to pre-exposure prophylaxis. In addition, the present disclosure relates to methods for fabricating compounds according to the disclosure.
2. Background Information
The human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS), a life threatening disease for which there is no cure. Since its discovery 30-years ago, there have been over 60 million people that have been infected with HIV and 25 million have died of HIV related causes. As of 2009, there were an estimated 33.3 million people living with the disease and 1.8 million new infections worldwide per year1.
The advent of highly active anti-retroviral therapy (HAART) for the chronic suppression of virus replication has dramatically increased the mean survival time and improved quality of life for individuals infected with HIV. More recently, pre-exposure prophylactic administration of anti-retroviral therapy has been provided to healthy individuals at high risk of contracting the disease to prevent infection. Pre-exposure prophylaxis (PrEP) studies have shown a reduction in the rate of transmission to 1.7 in every 100 children in mother-to-child transmission and 44 out of every 100 events in cohorts of men who have sex with men2-6.
HIV is a positive sense RNA virus. The viral genome is ˜10,000 bp and encodes viral capsid, nucleocapsid, matrix, reverse transcriptase (RT), protease, envelope proteins (Gp120 & Gp41), integrase, Tat, Rev, Vif, Vpu and Nef. A host cell is infected when HIV gp120 binds the host CD4 receptor. Next, the virus binds the CCR5, or CXCR4, co-receptor and undergoes a conformational change, forming a prefusion complex with the host cell, which folds to merge the virus and host cell lipid membranes. Once inside the cell, the virus uncoats and the RT primes the viral RNA genome for transcription of a DNA copy of the genome. The DNA copy of the genome is integrated by the viral integrase into the host genome. The integrated genome is transcribed by the host polymerase machinery and the virus protein Tat. The viral protein Rev binds the newly transcribed full length RNA and the complex is exported from the nucleus into the cytoplasm. In the cytoplasm, the viral genome is translated and processed by the viral protease. The nucleocapsid and capsid surround the viral genome and the newly formed virion buds from the infected cells.
There are over 30 FDA-approved drugs for the treatment of HIV. The viral proteins successfully targeted by these drugs include RT, protease, gp41 and integrase. Inhibitors of the HIV RT and proteases are the most numerous of the FDA-approved drugs. They are part of the first and second line of treatment regimens7-9. The current evidence supports the combination of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and a potent third agent from another class including non-nucleoside reverse transcriptase inhibitors (NNRTIs)1°. The use of NRTIs and NNRTIs in PrEP has reduced transmission from an infected individual to non-infected individual2,4-6. Specifically,                1. Nevaripine, AZT and lamivudine have been shown to prevent transmission from mother-to-child5; and        2. Emtricidine and tenofovir have been shown to prevent infection in discordant sexual transmissions in an oral formulation in a cohort of men who have sex with men2,4.        
Drug resistance to the HIV anti-viral drugs is well documented and is summarized biannually11. In the absence of a preventative vaccine and/or cure, new infections and lifelong anti-retroviral therapy will be a reality and mandates new antiviral agents to combat therapy resistant viruses.